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G Richter-Levin

Publications and source records attributed to G Richter-Levin.

At least 37 records · Page 2Linked to original sources
PubMed1996

Long-term potentiation increases tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit 2B in rat dentate gyrus in vivo.

Long-term potentiation (LTP) is a form of synaptic memory that may subserve developmental and behavioral plasticity. An intensively investigated form of LTP is dependent upon N-methyl-D-aspartate (NMDA) receptors and can be elicited in the dentate gyrus and hippocampal CA1. Induction of this type of LTP is triggered by influx of Ca2+ through activated NMDA receptors, but the downstream mechanisms of induction, and even more so of LTP maintenance, remain controversial. It has been reported that the function of NMDA receptor channel can be regulated by protein tyrosine kinases and protein phosphatases and that inhibition of protein tyrosine kinases impairs induction of LTP. Herein we report that LTP in the dentate gyrus is specifically correlated with tyrosine phosphorylation of the NMDA receptor subunit 2B in an NMDA receptor-dependent manner. The effect is observed with a delay of several minutes after LTP induction and persists in vivo for several hours. The potential relevance of this post-translational modification to mechanisms of LTP and circuit plasticity is discussed.

Amino Acid Sequence↗
PubMed1995

Dendritic spines form 'collars' in hippocampal granule cells.

A quantitative study of the distribution of dendritic spines was carried out in three orders of dendritic branches of granule cells from the dentate gyrus of the rat hippocampus. Golgi-stained preparations (7-19 neurones in each of seven rats) were analysed using computerized microscopy. Identification of spines and quantification of stem-spine geometry was performed using a segmentation algorithm and a line skeleton transformation of dendritic images. Analysis of data using the statistics of point processes revealed that, in all three branch orders, the distribution of visible spines along dendrites was not evenly random, but included dense clusters of spines surrounding the dendritic stem (spine 'collars'). Three-dimensional reconstructions from serial ultrathin sections have confirmed the presence of such spine groups. We speculate the spine collars represent a functional element in which associative synaptic plasticity is fostered by the proximity of individual synapses.

Animals↗
PubMed1995

Inhibitors of PLA2 and NO synthase cooperate in producing amnesia of a spatial task.

Both nitric oxide and arachidonic acid have been suggested to play a role as a retrograde messenger in synaptic plastic changes which underlie memory formation. However, inhibitors of nitric oxide (NO) synthesis or of arachidonic acid release have produced contradictory results. We suggest a model which involves simultaneous release of both messenger types which can compensate for the loss of one type. To test this theory, rats were injected either with a drug that inhibits release of arachidonic acid, or a drug that inhibits synthesis of NO, or with both drugs. Acquisition of a water maze task was not different between groups. In the test sessions, however, animals injected with both drugs showed marked amnesic symptoms, while the groups injected with a low dose of nordihydroguaiaretic acid (NDGA) or with nitro-L-arginine (L-NARG) showed a trend towards amnesia. The effect of both drugs appears to be additive. The results support the proposed theory.

Amino Acid Oxidoreductases↗
PubMed1995

Long-term potentiation and glutamate release in the dentate gyrus: links to spatial learning.

Long-term potentiation (LTP) in the dentate gyrus of the anaesthetized rat is associated with a persistent increase in the concentration of glutamate in the extracellular compartment. At the in vitro level, this is mirrored by an increase in the ability of slices or synaptosomes from potentiated tissue to release glutamate in response to a depolarizing stimulus. In both cases, the activity-induced enhancement of glutamate release is dependent on the activation of the NMDA receptor. A similar increase in glutamate release in vitro is observed in the dentate gyrus prepared from rats trained in a variety of learning tasks, including classical conditioning and the Morris water maze. These results are consistent with the hypothesis that similar presynaptic mechanisms are engaged in LTP and learning.

Animals↗
PubMed1995

Stimulation at 1-5 Hz does not produce long-term depression or depotentiation in the hippocampus of the adult rat in vivo.

1. We examined the efficacy of low-frequency trains (1-5 Hz) in producing long-term depression (LTD) or depotentiation in the hippocampus of the awake adult rat and in anesthetized rats aged from 10 days to 3 mo. 2. In the dentate gyrus we found no evidence that low-frequency trains produce either depotentiation or LTD in the awake, adult animal or in the anesthetized animal at any age tested (10 days-adult). 3. In area CA1 of both awake and anesthetized adult rats, we also found no evidence that low-frequency trains induced either LTD or depotentiation. Only in area CA1 of very young rats (10-11 days) was clear evidence for LTD and depotentiation obtained; at this age experiments were only possible in anesthetized animals. By 16 days, the ability to display both LTD and depotentiation was lost. 4. These experiments suggest that repetitive low-frequency stimulation evokes a developmentally regulated form of activity-dependent depression that in the hippocampus is limited to specific pathways in the young animal. Our results leave open the question of whether alternative patterns of activity can induce LTD and/or depotentiation in the adult awake rat.

Aging↗
PubMed1994

LTP in the dentate gyrus is associated with a persistent NMDA receptor-dependent enhancement of synaptosomal glutamate release.

LTP was induced unilaterally in the dentate gyrus of the anaesthetized rat by tetanic stimulation of the perforant path. Two hours after tetanization synaptosomes were prepared from control and potentiated sides, and the depolarization-induced release of endogenous amino acid neurotransmitters was compared in the two groups, using 4-aminopyridine, potassium or veratridine as depolarizing agents. Glutamate release was greater in synaptosomes from potentiated than control tissue with all three depolarizing agents, but the highest release from control synaptosomes and the most significant enhancement of release from potentiated synaptosomes was seen with veratridine. The tetanus-induced enhancement of veratridine-induced glutamate release was prevented by pretreatment with MK-801. The results indicate that the induction of LTP in the dentate gyrus is accompanied by a persistent enhancement in the ability of synaptosomes to release glutamate in response to a depolarizing stimulus.

4-Aminopyridine↗
PubMed1994

Differential effects of serotonin and raphe grafts in the hippocampus and hypothalamus: a combined behavioural and anatomical study in the rat.

Combined with a partial cholinergic deficiency, serotonergic lesions induce severe spatial learning deficits. Serotonergic lesions, however, have additional effects, such as reduced body weight and disruption of thermoregulation, which may be the cause of the observed learning deficits. Restoration of the serotonergic innervation of the hippocampus by raphe grafts reduces these learning deficits. The effects of the grafts may result from a direct support of spatial learning but may also be an indirect result of preventing some of the other effects of serotonergic lesions. In the present study we used raphe grafts to examine the selectivity and specificity of the effects of serotonergic lesions in the rat, and used the behavioural effects as an indication of successful transplantation in order to examine the fine details of such grafts. Raphe grafts in the hippocampus did not prevent the effects of the lesions on body weight, thermoregulation and exploratory behaviour but did minimize the effects of the lesions on spatial learning. In contrast, raphe grafts in the hypothalamus reduced the effects of the lesions on thermoregulation but failed to support learning. The grafted fibres showed termination specificity with the interneurons, which is typical of the serotonergic innervation of the normal hippocampus. The results indicate that the serotonergic innervation of the hippocampus functions locally to support spatial learning. This role of serotonin is independent of its involvement in modulation of body weight, thermoregulation or exploratory behaviour. The results confirm that the modes of serotonergic action in the hippocampus include the selective innervation of specific interneuron subpopulations.

5,7-Dihydroxytryptamine↗
PubMed1994

The effects of general and restricted serotonergic lesions on hippocampal electrophysiology and behavior.

Depletion of the forebrain serotonergic system was found in previous studies to induce an increased excitability of the dentate gyrus (DG) granule cells and, when combined with a cholinergic deficiency, to impair spatial learning. We now compared the effects of general forebrain serotonergic lesions induced by intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT), to those of a more restricted injection of 5,7-DHT into fornix-fimbria and cingulum, to eliminate hippocampal serotonergic innervation. Control and lesioned rats were injected with atropine and tested in the spatial learning water-maze task. Following the behavioral tests, rats were anesthetized and the responsiveness of the DG to perforant path (PP) stimulation was measured. To assess the lesions functionally, responses to application of the serotonin releasing drug fenfluramine (FFA) were measured. Finally, the reduction, in the hippocampus, of serotonergic innervation was evaluated by [3H]imipramine binding. The effects of the lesions on the responsiveness to FFA confirmed that the ICV lesions were functionally more general than the FF lesions. [3H]Imipramine binding indicated that both lesions reduced the serotonergic innervation of the hippocampus significantly. Behaviorally, both lesioned groups were impaired in the water-maze. Electrophysiologically, in both DG excitability was higher than in controls and in both hyperexcitability was associated with an increase in feed-forward inhibition. The results suggest that the serotonergic innervation of the hippocampus proper is involved in cognitive functions associated with the hippocampus.

Action Potentials↗
PubMed1994

Activation of metabotropic glutamate receptors is necessary for long-term potentiation in the dentate gyrus and for spatial learning.

We have examined the effects of the metabotropic glutamate receptor antagonist (RS)-a-methyl-4-carboxyphenylglycine (MCPG) on performance in the water maze, and on LTP in the dentate gyrus, MCPG (5 mM) reversibly blocked the induction of LTP in the perforant path-granule cell projection when perfused into the dentate gyrus of the anaesthetized rat. When injected bilaterally into the lateral ventricles, MCPG (20 mM) disrupted the performance of rats in a spatial learning version of the water maze task. In a terminal experiment, when tetanic stimulation was given to the perforant path, LTP, was found to be significantly reduced in MCPG-injected rats compared to control rats injected with vehicle. These experiments indicate that activation of MCPG-sensitive metabotropic glutamate receptors is necessary both for the full expression of LTP and spatial learning, and supply further evidence for the hypothesis that LTP provides synaptic mechanism for certain forms of learning.

Animals↗
PubMed1993

Age-related cognitive deficits in rats are associated with a combined loss of cholinergic and serotonergic functions.

The cholinergic hypothesis of senile dementia proposes that an age-dependent reduction of central cholinergic functions accounts for the severe cognitive deficits seen in aged rats. A careful examination of the experimental evidence cited in support of this hypothesis reveals that it cannot account for some behavioral observations. We have modified this hypothesis and wish to propose that serotonin and acetylcholine interact to allow normal cognitive functions in the brain. Thus, a partial reduction in both cholinergic and serotonergic functions will cause severe memory impairment in young as well as in aged rats. We found that restoration of the serotonergic innervation in the hippocampus of serotonin depleted rats, using tissue transplants, can restore impaired behavior. We have localized a memory-related interaction between serotonin and acetylcholine in the hippocampus and are in the process of identifying a physiological function which may underly this interaction.

Acetylcholine↗
PubMed1993

Regional specificity of raphe graft-induced recovery of behavioral functions impaired by combined serotonergic/cholinergic lesions.

We compared the effects of embryonic raphe grafted into either the hippocampus or the entorhinal cortex on the ability of rats to perform a spatial memory water-maze task. Serotonin depletion or partial cholinergic lesion of the hippocampus (by injection of colchicine into the septum) did not affect the ability of rats to perform the task, but the combined treatment did. Double-lesioned rats, with raphe grafts in the hippocampus, but not in the entorhinal cortex, performed similar to control or single-lesioned rats. The results suggest that the functioning of the serotonergic innervation of the hippocampus, and not of its afferents, is crucial for the ability of rats to perform spatial memory tasks, especially when the septohippocampal cholinergic connection is disrupted.

5,7-Dihydroxytryptamine↗
PubMed1992

Spontaneous recovery of deficits in spatial memory and cholinergic potentiation of NMDA in CA1 neurons during chronic lithium treatment.

The therapeutic action of lithium in affective disorders is still unclear. One effect of lithium is to deplete membrane inositol and consequently to exhaust the phosphoinositide (PI) pathway. Under chronic lithium treatment, rats showed persistent performance deficits in an active avoidance task and in a visually cued maze. The same treatment, however, resulted in only a transient deficit in the performance of rats in a spatial memory task. Lithium treatment caused a similarly transient deficit in the ability of acetylcholine to potentiate responses to N-methyl-D-aspartate (NMDA) in neurons of the hippocampal slice. The authors propose that the development of compensatory mechanisms may account for the lack of severe memory impairments during lithium treatment. It is suggested that the effects of lithium on the PI pathway are not sufficient to explain the behavioral consequences of chronic lithium treatment.

Acetylcholine↗
PubMed1992

Raphe grafts in the hippocampus, but not in the entorhinal cortex, reverse hippocampal hyperexcitability of serotonin-depleted rats and restore their responsiveness to fenfluramine.

We compared the effects of embryonic raphe grafted into either the hippocampus or the entorhinal cortex, on the responsiveness of dentate granule cells to stimulation of the perforant path. Raphe grafts in the hippocampus reversed the hyperexcitability of granule cells, resulting from depletion of the serotonergic innervation. Such grafts also restored the responsiveness of the granule cells to application of a serotonin releasing drug, fenfluramine (FFA). In contrast, hyperexcitability was not reversed when the graft was placed in the entorhinal cortex. Furthermore, although some increase in population spike size was observed in these rats after application of FFA, this increase had a response profile which was different from that of control and of lesioned rats that were grafted in the hippocampus. These results suggest that the serotonergic innervation, within the hippocampus and not in the entorhinal cortex, modulates granule cells excitability.

Animals↗
PubMed1991

Restoration of serotonergic innervation underlies the behavioral effects of raphe grafts.

It has been previously demonstrated that an embryonic raphe grafted into a serotonin-depleted hippocampus restores normal serotonin innervation of the hippocampus and behaviors associated with serotonin. To test the possibility that the behavioral effects of these grafts result from non-specific actions of the grafted tissue or the grafting procedure itself, we compared raphe grafts with septal grafts, in serotonin-depleted rats. We also compared the effects of a serotonin synthesis inhibitor, p-chlorophenylalanine, on the behavior of normal, serotonin-depleted and raphe-grafted rats. The results indicate that the bulk of behavioral effects of raphe grafts are due to the serotonergic nature of the graft.

5,7-Dihydroxytryptamine↗
PubMed1991

An alpha 2 antagonist, idazoxan, enhances EPSP-spike coupling in the rat dentate gyrus.

The effect of the alpha 2 antagonist, idazoxan (IDA), on the excitability of neurons in the dentate gyrus of the hippocampus was studied. Population field potentials (PS) evoked by stimulation of the perforant pathway were measured before and after drug treatment. IDA enhanced the amplitude of the PS, while decreasing the slope of the EPSP. Neurotoxic destruction of noradrenergic nerve terminals completely abolished the IDA effect, arguing that its mechanism of action is through enhanced release of noradrenaline (NA). It is proposed that NA enhances the EPSP-to-spike coupling component of the PS.

Adrenergic alpha-Antagonists↗
PubMed1991

Actions of norepinephrine in the rat hippocampus.

Acting at postsynaptic alpha 1- and beta 1-receptors, norepinephrine (NE) exerts a complex action in rat hippocampus. It is currently believed that beta 1-receptor activation enhances excitability of recorded neurons, whereas alpha 1 activation suppresses reactivity to afferent stimulation. These reported effects of alpha-agonists are not consistent with alpha 1 effects found elsewhere in the brain. We have conducted experiments in the anesthetized rat and found that an amphetamine-induced increase in the dentate gyrus population spike can be blocked by a beta-antagonist but also by an alpha 1-antagonist. We have conducted experiments in the brain slide preparation and found that an alpha-agonist, phenylephrine (PHE), selectively enhances responses to N-methyl-D-aspartate (NMDA) but not to quisqualate. We propose that the product of activation of both alpha- and beta-receptor types will enhance reactivity of hippocampal cells to afferent stimulation.

Afferent Pathways↗
PubMed1991

The effects of serotonin depletion and raphe grafts on hippocampal electrophysiology and behavior.

The involvement of the serotonergic system in spatial learning and a possible correlation between serotonergic modulation of hippocampal electrical activity and spatial learning were studied in rats. Control, partial septal-lesioned (SL), 5,7-dihydroxytryptamine (5,7-DHT)-injected (DHT), double-lesioned (5,7-DHT and SL; DL), and DL rats that were transplanted with embryonic raphe grafts into the hippocampus (RG) were tested in a spatial task in a water maze and in an active avoidance shuttle-box task. The responses of the dentate gyrus (DG) to perforant-path (PP) stimulation were examined in the same rats, under the following conditions: (1) priming stimulation of the PP (testing feedback inhibition), (2) priming stimulation of the commissural pathway (testing feedforward inhibition), (3) during repeated stimulation of the PP at 7 Hz (frequency potentiation), and (4) following tetanic stimulation [long-term potentiation (LTP)]. DL, but not DHT or SL, treatment severely impaired the performance of rats in both reference- and working-memory tasks in the water maze. This effect was not seen in the shuttle box. The ability of the DG to exhibit LTP, which was reduced in the DHT and SL rats, was apparently similar to controls in the DL group, DL, but not DHT or SL alone, resulted in a reduction of inhibition in the DG. Both the behavioral deficits and the reduction in hippocampal inhibition were ameliorated by intrahippocampal raphe grafts. These results indicate that the serotonergic innervation of the hippocampus plays a role in spatial learning when the septohippocampal neurotransmission systems are disrupted. Furthermore, these results suggest that restoration of modulation of hippocampal inhibition, by raphe grafts, underlies the behavioral recovery observed in these rats.

5,7-Dihydroxytryptamine↗